A peroxisome proliferator-activated receptor-gamma agonist, troglitazone, facilitates caspase-8 and -9 activities by increasing the enzymatic activity of protein-tyrosine phosphatase-1B on human glioma cells

J Biol Chem. 2006 Mar 10;281(10):6165-74. doi: 10.1074/jbc.M505266200. Epub 2005 Nov 30.

Abstract

Despite dramatic advances in adjuvant therapies, patients with malignant glioma face a bleak prognosis. Because many adjuvant therapies seek to induce glioma apoptosis, strategies that lower thresholds for the induction of apoptosis may improve patient outcomes. Therefore, elucidation of the biological mechanisms that underlie resistance to current therapies is needed to develop new therapeutic strategies. Here we proposed a novel mechanism of proapoptotic effect induced by a pharmacological peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, troglitazone, that facilitates caspase signaling in human glioma cells. Troglitazone activates protein-tyrosine phosphatase (PTP)-1B, which subsequently reduces phosphotyrosine 705 STAT3 (pY705-STAT3) via a PPARgamma-independent pathway. Reduction of pY705-STAT3 in glioma cells caused down-regulation of FLIP (FADD-like IL-1beta-converting enzyme-inhibitory protein) and Bcl-2. Furthermore, troglitazone induced Ser-392 phosphorylation of p53 via a PPARgamma-dependent pathway and up-regulation of Bax in a p53 wild-type glioma. When given with tumor necrosis factor-related apoptosis-inducing ligand or caspase-dependent chemotherapeutic agents, such as etoposide and paclitaxel, troglitazone exhibited a synergistic effect by facilitating caspase-8/9 activities. A PPARgamma antagonist, GW9662, did not block this effect, although a PTP inhibitor abrogated it. Knockdown of STAT3 by STAT3-small interfering RNA negated the inhibitory effect of PTP inhibitor on troglitazone, indicating that troglitazone uses a STAT3 inactivation mechanism that makes caspase-8/9 activities susceptible to cytotoxic agents in glioma cells and that PTP1B plays a critical role in the down-regulation of activated STAT3, as well as FLIP and Bcl-2. When taken with caspase-dependent anti-neoplastic agents, troglitazone may be a promising drug for use against malignant gliomas because it facilitates the caspase cascade, thereby lowering thresholds for the apoptosis induction of glioma cells.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins / drug effects
  • Apoptosis Regulatory Proteins / physiology
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Chromans / pharmacology*
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Glioma / drug therapy
  • Glioma / enzymology*
  • Glioma / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / physiology
  • PPAR gamma / agonists*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / biosynthesis
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • STAT3 Transcription Factor / physiology
  • TNF-Related Apoptosis-Inducing Ligand
  • Thiazolidinediones / pharmacology*
  • Troglitazone
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / physiology
  • Up-Regulation / drug effects*
  • Up-Regulation / physiology

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Chromans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • PPAR gamma
  • STAT3 Transcription Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Thiazolidinediones
  • Tumor Necrosis Factor-alpha
  • PTPN1 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases
  • Troglitazone